Polydextrose for the prevention and/or treatment of heart failure

ABSTRACT

The present invention concerns polydextrose for use for preventing and/or treating heart failure in a subject.

The present invention concerns the prevention and/or treatment of heartfailure, more particularly of heart failure of ischemic origin.

Half of the heart failure cases are of ischemic origin. Whenadministered in acute phase of myocardial infarction,angiotensin-converting-enzyme inhibitors and beta blockers have beendemonstrated as having a beneficial effect, in particular on cardiacremodeling. However, despite substantial progresses, the prognosis ofpatients suffering from heart failure due to ischemic cardiopathy is notgood, since the five-year mortality year is 50%.

Additionally, because of the improvement in the survival rate aftermyocardial infarction, there is an increase in the incidence of heartfailure after a myocardial infarction. For example, it has beendemonstrated in the large study in the Canadian population, that 36% ofthe patients hospitalized with a myocardial infarction developed a heartfailure de novo during their hospitalization and 50% of the remainingpatients developed a heart failure de novo within 1 year after themyocardial infarction occurred.

Accordingly, there is an important need of preventing and treating heartfailure, in particular heart failure of ischemic origin.

The present invention arises from the unexpected finding by theinventors that polydextrose, when administered before or after anischemic event, could have a beneficial effect on cardiac remodeling andfunction after the ischemic event, thereby preventing or treating asubsequent heart failure. More particularly, they showed thatpolydextrose treatment was associated with favorable hemodynamic andstructural consequences with a decrease in the left ventriculardilation, an increase in the shortening fraction, an increase in theleft ventricular ejection fraction and a decrease in the leftventricular end-diastolic pressure.

The inventors demonstrated that this beneficial effect was associatedwith a modification in the bacterial translocation to the heart, whichis observed further to the ischemic event.

The present invention thus concerns polydextrose for use for preventingand/or treating heart failure in a subject.

The present invention also concerns polydextrose for use for preventingcardiac remodeling and/or ventricle dilatation and/or for preventingsystolic dysfunction.

The present invention also concerns a method for preventing an increasein bacterial translocation to heart tissue in a subject who sufferedfrom a myocardial infarction, comprising administering to said subjectan effective amount of polydextrose.

DETAILED DESCRIPTION OF THE INVENTION Heart Failure

As used herein, the term “heart failure” refers to a condition whereinthe heart, via an abnormality of cardiac function (detectable or not),fails to pump blood at a rate commensurate with the requirements of themetabolizing tissues or is able to do so only with an elevated diastolicfilling pressure. Heart failure may be chronic or acute.

Preferably, in the context of the invention, the heart failure to betreated or prevented is acute heart failure.

Acute heart failure is defined as the rapid onset of symptoms and signsof heart failure secondary to abnormal cardiac function.

The heart failure may involve the left ventricle, the right ventricle orboth. Accordingly, the heart failure to be treated or prevented in thecontext of the invention may be selected from left heart failure, rightheart failure and global heart failure.

Furthermore, heart failure is generally divided into two differenttypes: heart failure due to reduced ejection fraction (also known asheart failure with ventricular systolic dysfunction) and heart failurewith preserved ejection fraction (also known as heart failure withpreserved ventricular systolic function or diastolic heart failure).

Accordingly, the heart failure to be treated or prevented in the contextof the invention may be selected from the group consisting of heartfailure with ventricular systolic dysfunction and heart failure withpreserved ventricular systolic function.

More particularly, the heart failure to be treated or prevented in thecontext of the invention may be selected from the group consisting ofheart failure with left ventricular systolic dysfunction, heart failurewith preserved left ventricular systolic function and right heartfailure.

Heart failure, in particular acute heart failure, may be due to multiplecauses and precipitating factors, such as decompensation of pre-existingchronic heart failure (e.g. cardiomyopathy); acute coronary syndromesincluding myocardial infarction, unstable angina with large extent ofischemia and ischemic dysfunction, mechanical complication of acutemyocardial infarction and right ventricular infarction; hypertensivecrisis, acute arrhythmia including ventricular tachycardia, ventricularfibrillation, atrial fibrillation or flutter and other supraventriculartachycardia; valvular regurgitation including endocarditis, rupture ofchordae tendinae and worsening of pre-existing valvular regurgitation;severe aortic valve stenosis; acute severe myocarditis; cardiactamponade; aortic dissection; post-partum cardiomyopathy; andnon-cardiovascular precipitating factors including lack of compliancewith medical treatment, volume overload, infections particularlypneumonia or septicaemia, severe brain insult, after major surgery,reduction in renal function, asthma, drug abuse, alcohol abuse andphaeochromocytoma.

Preferably, the heart failure, in particular the acute heart failure, tobe treated or prevented in the context of the invention is of ischemicorigin. More preferably, the heart failure, in particular the acuteheart failure, to be treated or prevented in the context of theinvention is due to myocardial infarction. Most preferably, the heartfailure, in particular the acute heart failure, to be treated orprevented in the context of the invention is heart failure with leftventricular systolic dysfunction due to myocardial infarction.

Alternatively, the heart failure, in particular the acute heart failure,to be treated or prevented in the context of the invention is ofnon-ischemic origin. It may in particular be heart failure with leftventricular systolic dysfunction of non-ischemic origin orpost-adriamycin chemotherapy heart failure.

Subject

In the context of the present invention, a “subject” denotes a human ornon-human mammal, such as a rodent (rat, mouse, rabbit), a primate(chimpanzee), a feline (cat), or a canine (dog). Preferably, the subjectis human. The subject according to the invention may be in particular amale or a female.

In a particular embodiment of the invention, the subject is at risk ofheart failure.

Preferably, the subject suffered from a myocardial infarction.

Polydextrose

As used herein, the term “polydextrose” refers to a low calorie polymerof glucose, which is resistant to digestion by the enzymes in thestomach. It includes polymers products of glucose which are preparedfrom glucose, maltose, oligomers of glucose or hydrolysates of starch,which are polymerized by heat treatment in a polycondensation reactionin the presence of an acid, e.g. Lewis acid, inorganic acid or organicacid, including monocarboxylic acid, dicarboxylic acid andpolycarbolxylic acid, such as the products prepared by the processesdescribed in the American patents U.S. Pat. No. 2,436,967, U.S. Pat. No.2,719,179, U.S. Pat. No. 4,965,354, U.S. Pat. No. 3,766,165, U.S. Pat.No. 5,051,500, U.S. Pat. No. 5,424,418, U.S. Pat. No. 5,378,491, U.S.Pat. No. 5,645,647, U.S. Pat. No. 5,773,604 and U.S. Pat. No. 6,475,552.

The term “polydextrose” also includes the polymer products of glucoseprepared by the polycondensation of glucose, maltose, oligomers ofglucose or starch hydrolyzates in the presence of a sugar alcohol, e.g.polypol, such as in the reactions described in the American patent U.S.Pat. No. 3,766,165.

Moreover, the term “polydextrose” includes the glucose polymers whichhave been purified by techniques described in the art, such as (a)neutralizing any acid associated therewith by base addition thereto, orby passing a concentrated aqueous solution of the polydextrose throughan adsorbent resin, a weakly basic ion exchange resin, a type IIstrongly basic ion-exchange resin, mixed bed resin comprising a basicion exchange resin or a cation exchange resin, as described in Americanpatents U.S. Pat. No. 5,667,593 and U.S. Pat. No. 5,645,647; or (b)decolorizing by contacting the polydextrose with activated carbon orcharcoal, by slurrying or by passing the solution through a bed of solidadsorbent or by bleaching with sodium chlorite, hydrogen peroxide, orthe like; (c) molecular sieving methods, like ultrafiltration, reverseosmosis, size exclusion and the like; (d) enzymatically treatingpolydextrose; or (e) any other recognized techniques known in the art.Among the purification processes used in the art, the following may beespecially mentioned: bleaching e.g. using hydrogen peroxide; membranetechnology; ion exchange e.g. removal of citric acid as described inAmerican patent U.S. Pat. No. 5,645,647, or removal of color/bittertaste; chromatographic separation with a strong cation exchanger;hydrogenation in combination with ion exchange or with ion exchange andchromatographic separation, as described in American patent U.S. Pat.No. 5,424,418; or solvent extraction.

The term “polydextrose” further includes hydrogenated polydextrose,which, as used herein, includes hydrogenated or reduced polyglucoseproducts prepared by techniques known from the skilled person, such astechniques described in American patents U.S. Pat. No. 5,601,863, U.S.Pat. No. 5,620,871 or U.S. Pat. No. 5,424,418.

The term “polydextrose” also encompasses fractionated polydextrose,which is a conventional, known material and can be produced e.g. by theprocesses disclosed in the American patent U.S. Pat. No. 5,424,418.

In a preferred embodiment, the polydextrose is purified polydextrose. Inanother preferred embodiment, the polydextrose is hydrogenated orreduced polydestrose. In a particularly preferred embodiment, thepolydextrose is both purified and hydrogenated.

It is preferred that the polydextrose used is substantially pure. Thepolydextrose may be made substantially pure using conventionaltechniques known from the skilled person, such as chromatography,including column chromatography, HPLC and the like. It is particularlypreferred that the polydextrose used is at least 80% pure, i.e. at leastabout 80% of the impurities are removed. More preferably, it is at least85% pure or even more preferably at least 90% pure.

Medical Use

The present invention concerns polydextrose, as defined in the section“Polydextrose” above for use for preventing and/or treating heartfailure, as defined in the section ‘Heart failure” above, in a subject,as defined in the section “Subject” above.

The present invention further concerns the use of polydextrose, asdefined in the section “Polydextrose” above, in the manufacture of amedicament intended for the prevention and/or the treatment of heartfailure, as defined in the section “Heart failure” above, in a subject,as defined in the section “Subject” above.

Another object of the invention concerns a method of preventing and/ortreating heart failure, as defined in the section “Heart failure” above,in a subject, as defined in the section “Subject” above, in needthereof, comprising administering to said subject a therapeuticallyeffective amount of polydextrose, as defined in the section“Polydextrose” above.

In the context of the invention, the term “treating” or “treatment”, asused herein, means reversing, alleviating, inhibiting the progress ofthe disorder or condition to which such term applies, or one or moresymptoms of such disorder or condition.

“Preventing” refers to measures taken to prevent the disorder orcondition to which such term applies from occurrence or, in early stagesof a disease or disorder.

A “therapeutically effective amount” refers to a quantity of activeagent that confers a therapeutic effect on the treated subject. Thetherapeutic effect may be objective (i.e. measurable by some test ormarker) or subjective (i.e. subject gives an indication of or feels aneffect). As known from the skilled person, effective doses will varydepending on route of administration, the size and/or weight of thesubject, as well as the possibility of co-usage with other agents.

Any suitable method of administration known from one skilled in the artmay be used. In particular, polydextrose may be administered for exampleby the oral route.

Polydextrose for oral administration may be in the form of, for example,aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, ormay be presented as a dry product for constitution with water or othersuitable vehicle before use. Such liquid pharmaceutical compositions maycontain conventional additives such as suspending agents, emulsifyingagents, non-aqueous vehicles (which may include edible oils), orpreservatives.

Polydextrose may be included in pharmaceutical compositions furthercontaining excipients such as flavorings, colorings, anti-microbialagents, or preservatives.

The dose range depends on the composition to be administered. As is wellknown in the medical arts, dosages for any one subject depend on manyfactors, including the patient's size, body surface area, age, theparticular compound to be administered, sex, time and route ofadministration, general health, and other drugs being administeredconcurrently. Preferably, polydextrose is administered at a dose of 12 gto 90 g per day.

In the context of the invention, polydextrose is preferably administeredto the subject to be treated after myocardial infarction occurred, morepreferably as soon as possible after myocardial infarction occurred. Inparticular, polydextrose may be administered to the subject to betreated 1 to 12 hours after myocardial infarction occurred, 1 day aftermyocardial infarction occurred, 2 days after myocardial infarctionoccurred or even 3 days after myocardial infarction occurred.

Alternatively, polydextrose can be administered before occurrence ofmyocardial infarction, in particular in subjects at risk of myocardialinfarction, and can optionally still be administered after theoccurrence of myocardial infarction. In a particular embodiment,polydextrose is administered in a subject at risk of myocardialinfarction.

By “subject at risk of myocardial infarction” is meant herein a subjectdisplaying known risk factors of occurrence of myocardial infarction.Such risk factors are well-known from the skilled person and includeobesity, smoking, diabetes, high blood pressure, hyperlipidemia andfamily history of myocardial infarction.

The present inventors demonstrated more particularly that administrationof polydextrose in a model of myocardial infarction enabledsignificantly improving the end-diastolic and end-systolic volumes,which showed a prevention of ventricle, in particular left ventricle,dilatation.

They also showed that administration of polydextrose in the same modelenabled significantly decreasing left ventricular end-diastolicpressure, improving developed pressure and improving cardiaccontractility parameters such as contraction (+dP/dtmax) and relaxation(dP/dtmin).

The present invention thus further concerns polydextrose, as defined inthe section “Polydextrose” above for use for preventing and/or treatingheart failure, as defined in the section ‘Heart failure” above, in asubject, as defined in the section “Subject” above, for preventingcardiac remodeling and/or ventricle dilatation.

The present invention further concerns the use of polydextrose, asdefined in the section “Polydextrose” above, in the manufacture of amedicament intended for the prevention and/or the treatment of heartfailure, as defined in the section “Heart failure” above, in a subject,as defined in the section “Subject” above, for the prevention of cardiacremodeling and/or ventricle dilatation.

Another object of the invention concerns a method of preventing cardiacremodeling and/or ventricle dilatation in a subject, as defined in thesection “Subject” above, in need thereof, comprising administering tosaid subject a therapeutically effective amount of polydextrose, asdefined in the section “Polydextrose” above.

As used herein, “ventricle dilatation” refers to an increase in size ofventricular cavity. Ventricular dilatation can typically be determinedby measuring end-diastolic and end-systolic volumes by techniqueswell-known from the skilled person. It can also be represented by theejection fraction which is the ratio between the stroke volume(difference between the end-diastolic volume and the end-systolicvolume) and the end-diastolic volume: a reduced ejection fractionindicates ventricle dilatation.

Ventricle dilatation is more particularly observed in cases of heartfailure with ventricular systolic dysfunction. Accordingly, in aparticular embodiment, polydextrose is for use for preventing ventricledilatation for treating and/or preventing heart failure with ventricularsystolic dysfunction.

As used herein, “cardiac remodeling” or “ventricular remodeling” refersto the changes in size, shape, structure and physiology of the heartafter injury to the myocardium.

The present invention thus further concerns polydextrose, as defined inthe section “Polydextrose” above for use for preventing and/or treatingheart failure, as defined in the section ‘Heart failure” above, in asubject, as defined in the section “Subject” above, for preventingsystolic dysfunction.

The present invention further concerns the use of polydextrose, asdefined in the section “Polydextrose” above, in the manufacture of amedicament intended for the prevention and/or the treatment of heartfailure, as defined in the section “Heart failure” above, in a subject,as defined in the section “Subject” above, for the prevention ofsystolic dysfunction.

Another object of the invention concerns a method of preventing systolicdysfunction in a subject, as defined in the section “Subject” above, inneed thereof, comprising administering to said subject a therapeuticallyeffective amount of polydextrose, as defined in the section“Polydextrose” above.

As used herein, “systolic dysfunction” refers to ventricular failurecharacterized by a reduced ejection fraction and an enlarged ventricularchamber.

The present inventors demonstrated that polydextrose treatment modifythe intestinal and cardiac tissue microbiota in a myocardial infarctionmurine model and prevents notably the increase in bacterial DNA incardiac tissues in acute phase of infarction in mice

The present invention thus further concerns a method for preventing anincrease in bacterial translocation to heart tissue in a subject whosuffered from a myocardial infarction, comprising administering to saidsubject an effective amount of polydextrose, as defined in the section“Polydextrose” above.

As used herein, “bacterial translocation” refers to the passage ofviable bacteria from the gastrointestinal tract to extraintestinalsites.

In the context of the invention, polydextrose may be administered incombination with conventional therapies of heart failure, in particularof acute heart failure, and/or post-myocardial infarction.

Conventional therapies of heart failure and/or post-myocardialinfarction are well-known from the skilled person and include morphineand its analogues, anticoagulation therapy, vasodilators includingnitrates, sodium nitroprusside, nesiritide and calcium antagonists,angiotensin converting enzyme inhibitors, diuretics, β-blocking agents,inotropic agents including dopamine, dobutamine, phosphodiesteraseinhibitors, levosimendan and cardiac glycosides.

The present invention will be further illustrated by the figures andexamples below.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the left ventricular end-diastolic volume (in cm³) ofhearts of:

mice which underwent a thoracotomy but no coronary ligation (Sham),

mice which were treated with polydextrose 7 days before the surgery andduring 28 days after the thoracotomy without coronary ligation (Sham+PBSd-7),

mice which underwent a thoracotomy with coronary ligation (MI),

mice which underwent a thoracotomy with coronary ligation and weretreated with polydextrose 7 days before and during 28 days after thesurgery (MI+PDX d−7), and

mice which underwent a thoracotomy with coronary ligation and weretreated with polydextrose 3 days after and during 25 days after theoperation (MI+PDX d+3), as disclosed in the example below.

FIG. 1 demonstrated that administration of PDX, before and after leftcoronary ligation, ameliorates significantly left ventricular dilation(estimated by left ventricular end-diastolic volume), as compared withthe MI group.

a: P<0.05 versus Sham; b: P<0.05 versus MI.

FIG. 2 shows the left ventricular end-systolic volume (in cm³) of heartsof mice which underwent a thoracotomy but no coronary ligation (Sham),mice which were treated with polydextrose 7 days before and during 28days after the thoracotomy without coronary ligation (Sham+PBS d−7),mice which underwent a thoracotomy with coronary ligation (MI), micewhich underwent a thoracotomy with coronary ligation and were treatedwith polydextrose 7 days before and during 28 days after the surgery(MI+PDX d−7), and mice which underwent a thoracotomy with coronaryligation and were treated with polydextrose 3 days after and during 25days after the surgery (MI+PDX d+3), as disclosed in the example below.

FIG. 2 demonstrated that administration of PDX, before and after leftcoronary ligation, ameliorates significantly left ventricular dilation(estimated by left ventricular end-systolic volume), as compared withthe MI group.

a: P<0.05 versus Sham; b: P<0.05 versus MI.

FIG. 3 shows the left ventricular ejection fraction (% EF) of hearts ofmice which underwent a thoracotomy but no coronary ligation (Sham), micewhich were treated with polydextrose 7 days before and during 28 daysafter the thoracotomy without coronary ligation (Sham+PBS d−7), micewhich underwent a thoracotomy with coronary ligation (MI), mice whichunderwent a thoracotomy with coronary ligation and were treated withpolydextrose 7 days before and during 28 days after the surgery (MI+PDXd−7), and mice which underwent a thoracotomy with coronary ligation andwere treated with polydextrose 3 days after and during 25 days after thesurgery (MI+PDX d+3), as disclosed in the example below.

FIG. 3 demonstrated that PDX treatment both prevented or rescued thedecrease of cardiac function, estimated by the % of ejection fraction,following 28 days of MI.

a: P<0.05 versus Sham; b: P<0.05 versus MI.

FIG. 4 shows the left ventricular end-diastolic pressure (mmHg) ofhearts of mice which underwent a thoracotomy but no coronary ligation(Sham), mice which were treated with polydextrose 7 days before andduring 28 days after the thoracotomy without coronary ligation (Sham+PBSd−7), mice which underwent a thoracotomy with coronary ligation (MI),mice which underwent a thoracotomy with coronary ligation and weretreated with polydextrose 7 days before and during 28 days after thesurgery (MI+PDX d−7), and mice which underwent a thoracotomy withcoronary ligation and were treated with polydextrose 3 days after andduring 25 days after the surgery (MI+PDX d+3), as disclosed in theexample below.

FIG. 4 demonstrated that administration of PDX, before and after leftcoronary ligation, ameliorates significantly the decreased leftventricular end-diastolic pressure observed in the MI group.

a: P<0.05 versus Sham; b: P<0.05 versus MI.

FIG. 5 shows the left ventricular developed pressure (mmHg) of hearts ofmice which underwent a thoracotomy but no coronary ligation (Sham), micewhich were treated with polydextrose 7 days before and during 28 daysafter the thoracotomy without coronary ligation (Sham+PBS d−7), micewhich underwent a thoracotomy with coronary ligation (MI), mice whichunderwent a thoracotomy with coronary ligation and were treated withpolydextrose 7 days before and during 28 days after the surgery (MI+PDXd−7), and mice which underwent a thoracotomy with coronary ligation andwere treated with polydextrose 3 days after and during 25 days after thesurgery (MI+PDX d+3), as disclosed in the example below.

FIG. 5 demonstrated that administration of PDX, before and after leftcoronary ligation, ameliorates significantly the decreased developedpressure observed in the MI group.

a: P<0.05 versus Sham; b: P<0.05 versus MI.

FIG. 6 shows (A) the left ventricular contraction dP/dtmax (mmHg/s) and(B) the left ventricular relaxation dP/dtmin (mmHg/s) of hearts of micewhich underwent a thoracotomy but no coronary ligation (Sham), micewhich were treated with polydextrose 7 days before and during 28 daysafter the thoracotomy without coronary ligation (Sham+PBS d−7), micewhich underwent a thoracotomy with coronary ligation (MI), mice whichunderwent a thoracotomy with coronary ligation and were treated withpolydextrose 7 days before and during 28 days after the surgery (MI+PDXd−7), and mice which underwent a thoracotomy with coronary ligation andwere treated with polydextrose 3 days after and during 25 days after thesurgery (MI+PDX d+3), as disclosed in the example below.

FIG. 6 demonstrated that administration of PDX, before and after leftcoronary ligation, ameliorates significantly both the decreased cardiaccontractility (estimated by the LV dP/dtmax index) and relaxation(estimated by the LV dP/dtmin index) observed in the MI group.

a: P<0.05 versus Sham; b: P<0.05 versus MI.

FIG. 7 shows the concentration of bacterial DNA encoding the 16Sribosomal RNA (ng/μg total DNA) in (A) blood or (B) heart of mice whichunderwent a thoracotomy but no coronary ligation (Sham) or mice whichunderwent a thoracotomy with coronary ligation (MI), 12 hours, 1 day and3 days after the operation.

FIG. 7 demonstrated that MI surgery induced a significant increase inbacterial translocation both in the blood and the heart of operatedmice.

a: P<0.05 versus Sham 12 h post-surgery; b: P<0.05 versus Sham 1 daypost-surgery; c: P<0.05 versus Sham 3 days post-surgery.

FIG. 8 shows the level (percentage of total reads), determined bytargeted metagenomics sequencing, of different bacterial family in thecardiac tissue of mice who underwent a thoracotomy with coronaryligation (MI) and of mice which underwent a thoracotomy with coronaryligation and were treated with polydextrose.

FIG. 9 shows the level (percentage of total reads), determined bytargeted metagenomics sequencing, of different bacterial family in thecardiac tissue of mice who underwent a thoracotomy with coronaryligation (MI) and of mice which underwent a thoracotomy with coronaryligation and were treated with polydextrose.

FIG. 10 shows the concentration of bacterial DNA encoding the 16Sribosomal RNA (ng/μg total DNA) in cardiac tissue of hearts from healthysubjects (NF) and from subjects suffering from hypokinetic dilatedcardiomyopathy (DCM).

a: P<0.05 versus NF.

EXAMPLE

The inventors carried out an experimental study in mice in a murinemodel of myocardial infarction.

Materials and Methods Treatment of Mice

Five groups of mice were formed.

The first control group of mice (Sham) underwent a thoracotomy but nocoronary ligation.

The second group of mice (Sham+PDX) was treated with polydextrose 7 daysbefore and during 28 days after the thoracotomy (without coronaryligation).

The third group of mice (MI) underwent a thoracotomy with coronaryligation.

The fourth group of mice (MI+PDX d−7) underwent a thoracotomy withcoronary ligation and was treated with polydextrose 7 days before andduring 28 days after the surgery.

The fifth group of mice (MI+PDX d+3) underwent a thoracotomy withcoronary ligation and was treated with polydextrose 3 days after andduring 25 days after the surgery.

The treatment with polydextrose was administered daily by gavage 0.2g/mice/day).

Polydextrose used was Litesse Ultra polydextrose commercialized byDupont.

Cardiac surgery

Myocardial infarction (MI) was performed on 8 week-old male C57BU6J. Inbrief, male 8 week-old mice were anesthetized by an intraperitoneal(i.p.) injection of a cocktail of ketamine (100 mg/kg) and xylazine (10mg/kg), intubated, and connected to a mouse ventilator (MiniVent,Harvard Apparatus, Holliston, Mass.). Permanent ligation of the leftanterior descending artery was blocked using a segment of saline 9-0prolene. The sham group (without ligation of the left anteriordescending artery) was set up as the control group. All surgicalprocedures were performed under sterile conditions. Successful cardiacinfarction was confirmed by apparent S-T segment elevation. 4 weekspost-surgery, echocardiography and left ventricular catheter wereperformed; subsequently, cardiac tissues from different regions wereharvested for further analysis.

Echocardiography

Non-invasive ultrasound examination of the cardiovascular system wasperformed using a General Electric instrument equipped with a linear8-14-MHz transducer. The surgeon and echocardiographer were blinded toanimal genotype.

Hemodynamic Analysis Using Intraventricular Catheterization

Adult mice were anesthetized in order to produce a near physiologicheart rate of 500 beats/min. The mice were intubated and ventilated witha Harvard ventilator set at 200-400 μl. The bilateral carotid arterieswere identified in the region of the trachea and the right carotid wascannulated with a 1.0 French mouse pressure catheter (Millar, SPR-1000).The catheter was advanced retrogradely through the aortic valve into theleft ventricle to assess pressure volume loops. LV systolic anddiastolic pressures, the derivative of LV pressure (dP/dT), and tau wererecorded and analysed with Emka analysis software (iox2).

Measurement of Blood Concentration of the Bacterial Gene Encoding the16S Ribosomal RNA

Total bacterial DNA was extracted from snap-frozen feces, blood andcardiac tissue specimen using the QlAamp DNA mini stool kit (Qiagen,Courtaboeuf, France), which also included homogenization using a (≤106μm diameter) bead-beating step (6,500 rpm, 3×30 s). The inventorsstudied the 16S rDNA gene as some regions of this gene are highlyconserved between different species of bacteria and it is considered amarker of the overall microbiota. The 16S rDNA sequences that belong tothe

Proteobacteria phylum (Pbac) were measured. The DNA was amplified byreal-time PCR (Stepone+; Applied Biosystems) in optical grade 96-wellplates. The PCR was performed in a total volume of 25 μl using the PowerSYBR® Green PCR master mix (Applied Biosystems), containing 300 nM ofeach of the universal forward and reverse primers.

The deep sequencing of the tissue microbiota was performed by 16S rDNAMiSeq sequencing. 450 bp sequences were obtained and analyzed usingMothur software.

Results

The inventors studied the hemodynamic consequences and the consequenceson cardiac remodeling associated with polydextrose treatment(administered preventively or curatively).

They observed, in treated animals compared to non-treated animals, whichunderwent a myocardial infarction:

by echocardiography: a lesser dilatation of the left ventricular cavity(significant improvement of left ventricular end-diastolic andend-systolic volumes, as shown on

FIGS. 1 and 2), associated with a significant improvement of the leftventricular ejection fraction (% EF), as shown on FIG. 3.

by hemodynamic analysis using intraventricular catheterization: areduction in the left-ventricular end-diastolic pressure, as shown onFIG. 4, an improvement of the left ventricular developed pressure, asshown on FIG. 5, and an improvement in the cardiac contractilityparameters (contraction +dP/dtmax and relaxation dP/dtmin), as shown onFIG. 6.

The inventors further studied the intestinal and cardiac tissuemicrobiota to analyze the effect of polydextrose on bacterialtranslocation.

Intestinal and cardiac tissue microbiota was analyzed by sequencing thebacterial gene encoding the 16S ribosomal RNA. Blood concentration ofthe bacterial gene encoding the 16S ribosomal RNA was measured beforeand after myocardial infarction.

The inventors observed that a myocardial infarction induces a bacterialtranslocation, as soon as 12 hours post-surgery, in blood and cardiactissues, with an accumulation of the bacterial level in the infarctedzone (IZ-MI) and in the still living zone of the left ventricle (LV-MI),as shown on FIG. 7.

They further observed qualitatively, in untreated mice which underwent amyocardial infarction (MI), a change in the intestinal and cardiactissue microbiota compared to control animals (Sham). Additionally,polydextrose-treated mice which underwent a myocardial infaction(MI+PDX) displayed a different microbiota compared to MI mice, toSham+PDX mice and to Sham mice. Furthermore, the inventors showed that,quantitatively, polydextrose reduced bacterial translocation in thecardiac tissue in MI+PDX mice compared to MI mice (FIGS. 8 and 9).

The inventors further measured the concentration of the bacterial geneencoding 16S ribosomal RNA in human cardiac tissues, from heartswithdrawn from heart-transplanted patients suffering from hypokineticdilated cardiomyopathy or from hearts from healthy donors and intendedto be transplanted in patients suffering from heart failure. They showedan increase in the concentration of bacterial DNA encoding 16S ribosomalRNA in hearts from heart-transplanted patients, as shown on FIG. 10.

These results thus show that polydextrose treatment modify theintestinal and cardiac tissue microbiota in a myocardial infarctionmurine model and prevents notably the increase in bacterial DNA incardiac tissues in acute phase of infarction in mice. This is associatedwith favorable hemodynamic and structural consequences with a decreasein the left ventricular dilation, an increase in the shorteningfraction, an increase in the left ventricular ejection fraction and adecrease in the left ventricular end-diastolic pressure. The inventorsfurther confirmed the relevance of these results in humans, bydemonstrating that an increase in bacterial DNA concentration could beobserved in cardiac tissue of hearts from patients suffering fromhypokinetic dilated cardiomyopathy.

1. A method for preventing and/or treating heart failure in a subject inneed thereof, comprising administering to said subject a therapeuticallyeffective amount of polydextrose.
 2. The method according to claim 1,wherein said heart failure is acute heart failure.
 3. The methodaccording to claim 1, wherein said heart failure is selected from leftheart failure, right heart failure and global heart failure.
 4. Themethod according to claim 1, wherein said heart failure is selected fromthe group consisting of heart failure with ventricular systolicdysfunction and heart failure with preserved ventricular systolicfunction.
 5. The method according to claim 1, wherein said heart failureis of ischemic origin.
 6. The method according to claim 1, wherein saidsubject suffered from a myocardial infarction.
 7. The method accordingto claim 1, for preventing cardiac remodeling and/or ventricledilatation.
 8. The method according to claim 1, for preventing systolicdysfunction.
 9. The method according to claim 6, wherein polydextrose isadministered to said subject after myocardial infarction occurred. 10.The method according to claim 1, wherein said polydextrose is purifiedpolydextrose.